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- Tesi, Bianca, et al.
(författare)
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Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors : a nationwide, prospective Swedish study
- 2024
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Ingår i: The Lancet Regional Health. - : Elsevier. - 2666-7762. ; 39
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundChildhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors.MethodsgWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients.FindingsThe prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed de novo in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35).InterpretationOverall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients.
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| 2. |
- Tesi, Bianca, et al.
(författare)
-
Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors : a nationwide, prospective Swedish study
- 2024
-
Ingår i: The Lancet Regional Health. - : Elsevier. - 2666-7762. ; 39
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Childhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors.Methods: gWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients.Findings: The prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed de novo in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35).Interpretation: Overall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients.Funding: The study was supported by the Swedish Childhood Cancer Fund and the Ministry of Health and Social Affairs.
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| 3. |
- Fili, Maria
(författare)
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Aspects of dose, dose rate and radioisotopes in brachytherapy of uveal melanoma
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Uveal melanomas constitute melanomas arising from the choroid, the ciliary body or the iris, and in adults stands for the most common primary malignant intraocular tumor. It has a high risk of metastatic spread followed by inevitable death, and unfortunately the prognosis has not improved over the last decades. In the beginning the only considerable treatment was enucleation, i.e. removal of the entire eye. However, brachytherapy has since the 70’s become the primary treatment for medium sized tumors, and the survival rate has been shown to be equal compared to primary enucleation. The aim of our studies included in this thesis was to investigate the efficacy of today’s brachytherapy treatment regime and if any differences in ocular or patient survival could be found considering different brachytherapy aspects. When investigating only ruthenium-106 brachytherapy, no association was found between high or low dose rate and the risk of secondary enucleation, i.e. enucleation due to extensive unwanted side effects, insufficient treatment effect on the tumor or tumor relapse. In further analysis with both ruthenium-106 and iodine-125 brachytherapy included in the study and the risk of tumor related mortality considered, there was no statistical difference in outcome related to either dose or dose rate applied and we found no negative consequences for patients that received lower dose and dose rates than intended. As there is a gender difference in survival outcome for some cancers, we investigated this issue regarding uveal melanoma, but no differences could be found indicating this should be a factor to consider when planning treatment. Ruthenium-106 brachytherapy is generally used throughout Europe. In Sweden, iodine-125 for larger medium sized tumors became available 20 years after ruthenium-106 brachytherapy had begun. We therefore had a great opportunity to analyze the larger tumors treated with ruthenium-106 in the earlier years and compare them to same size tumors treated with iodine-125. There was no difference in survival between matched groups, but ruthenium-106-treated patients had a significantly higher risk of needing retreatment, thus making iodine-125 the preferred nuclide for thicker tumors. In conclusion gender is not a factor that needs considering when planning treatment for uveal melanoma. Treatment with brachytherapy is both safe and effective within the current recommended doses and dose rates. Our findings suggest that lower doses and dose rates still would be adequate, and this should be investigated further. The current protocol for radioisotope selection based on tumor thickness also seems adequate for the best possible ocular and survival outcome.
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